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Conformational changes of the p53‐binding cleft of MDM2 revealed by molecular dynamics simulations
Author(s) -
EspinozaFonseca L. M.,
TrujilloFerrara José G.
Publication year - 2006
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.20566
Subject(s) - mdm2 , molecular dynamics , in silico , chemistry , preprint , dynamics (music) , biophysics , computational biology , suppressor , mechanism (biology) , nanotechnology , biochemistry , computer science , physics , computational chemistry , biology , materials science , world wide web , quantum mechanics , acoustics , gene
Two 35‐ns molecular dynamics simulations of both ligated [mouse double minute protein 2 (MDM2 p53 )] and unligated (MDM2 apo ) structures of human MDM2 bound to the N‐terminal domain of the tumor suppressor p53 have been performed. Analysis of the dynamics revealed that the most flexible region of MDM2 was the p53‐binding cleft. When MDM2 was bound to p53, a wider and more stable topology of the cleft was obtained, while unligated MDM2 showed a narrower and highly flexible cleft. It was also found that the dynamics involved in the opening/closing motions were due to the movement of different domains of the protein, which is in agreement with recent experimental data. Considering our results, a mechanism in which p53 might be recognized and attached to MDM2 is proposed, and some implications on future directions for in silico anticancer drug design efforts are discussed. In summary, the observations made here would be very useful not only for better understanding of the biological implications of the MDM2 dynamics, but also for future efforts in anticancer drug design and discovery. © 2006 Wiley Periodicals, Inc. Biopolymers 83:365–373, 2006 This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com